CN101981038B - Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors - Google Patents
Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors Download PDFInfo
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- 0 *C(*)(OC1c(cccc2)c2-c2c(*)c(ccc(*)c3)c3[n]2C2)OC12C(N(*)*)=O Chemical compound *C(*)(OC1c(cccc2)c2-c2c(*)c(ccc(*)c3)c3[n]2C2)OC12C(N(*)*)=O 0.000 description 3
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Abstract
The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.
Description
The cross reference of related application
The application requires in the rights and interests of the U.S. Provisional Patent Application 61/039967 of submission on March 27th, 2008.
Technical field
The application relates generally to new-type I compound, comprises their salt, and described compound has the activity of anti-hepatitis c virus (HCV), and can be used for treating those patients that infection has HCV.The application also relates to the method that contains these compound compositions and use these compounds.
Background technology
Hepatitis C virus (HCV) is main human pathogen, and it worldwide infects estimates 100,017,000 people, roughly is 5 times of 1 type HIV (human immunodeficiency virus) infection quantity.Sizable part develops into serious carrying out property hepatic diseases in these HCV infected individuals, comprises liver cirrhosis and hepatocellular carcinoma (Lauer, G.M.; Walker, B.D.N.Engl.J.Med.2001,345,41-52).
HCV is positive chain RNA virus.Based on the extensive similarity of the comparison and 5 ' that the deduction aminoacid sequence is carried out-non-translational region, HCV has been classified as in the flaviviridae independently and belonged to.All members of flaviviridae have the virosome of sealing, and the positive chain RNA genome that it contains is by translating single continuous open reading-frame (ORF) all known viral specificity protein of encoding.
In the genomic Nucleotide of whole HCV and coded aminoacid sequence, found the heterogeneity of certain degree.Characterize at least 6 kinds of main genotype, and described the hypotype more than 50 kinds.The oligogene type distribution worldwide of HCV is different, and the clinical importance of HCV genetic heterogeneity remains and be difficult to determine, although genotype has been gone a large amount of research to may influencing of morbidity and treatment.
The length of strand HCV rna gene group approximately is 9500 Nucleotide, and has single open reading-frame (ORF) (ORF), the single big polyprotein that its coding is made up of about 3000 amino acid.In infected cells, this polyprotein in a plurality of sites by leukoprotease and virus protease cracking, thereby produce structural protein and non-structure (NS) albumen.With regard to HCV, the generation of ripe Nonstructural Protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is subjected to the influence of two kinds of virus proteases.Think that first kind of virus protease is metalloprotease, and carry out cracking at the NS2-NS3 joint; Second kind of virus protease is included in the interior serine protease (being also referred to as NS3 proteolytic enzyme) of N-stub area of NS3, and all cracking subsequently in mediation NS3 downstream, both carry out cracking at the NS3-NS4A cracking site with cis, carried out cracking in remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B site with trans again.As if NS4A albumen has multiple function, and it serves as the cofactor of NS3 proteolytic enzyme, and may help the film location of NS3 and other rdrp virus component.NS3 albumen and NS4A form mixture, and it is necessary that this seemingly improves proteolysis efficient thus in all sites activity of processing.NS3 albumen also demonstrates nucleoside triphosphate enzyme and rna helicase enzymic activity.NS5B (being also referred to as the HCV polysaccharase) is the RNA polymerase that depends on RNA, relates to described enzyme in the copying of HCV.At " Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides (Bressanelli; S.et al., Journal of Virology 2002,3482-3492) with Defrancesco and Rice, Clinics in Liver Disease 2003,7 has described HCV NS5B albumen among the 211-242.
At present, the most effective HCV therapy is used the combination of alpha-interferon and ribavirin, its in 40% patient, produces lasting effect (Poynard, T.et al.Lancet 1998,352,1426-1432).Up-to-date clinical effectiveness proves, as monotherapy, the alpha-interferon of PEGization be better than the alpha-interferon of unmodified (Zeuzem, S.et al.N.Engl.J.Med.2000,343,1666-1672).Yet even with regard to the experimental treatment plan that relates to the combination of PEGization alpha-interferon and ribavirin, the continuous decrease of virus load does not appear in considerable patient yet.Therefore, with regard to effective therapy that exploitation is used for the treatment of the HCV infection, exist obviously and exigence.
The invention provides following technical benefits, for example described compound is new compound and effective anti-hepatitis C.In addition, described compound provides the benefit for pharmaceutical use, one or more benefits in the following areas for example: their mechanism of action, joint efficiency, suppress efficient, target selectivity, solvability, safety performance (safety profiles) or bioavailability.
HCV NS5B inhibitor has been disclosed in United States Patent (USP) 7,399, in 758.
Summary of the invention
The present invention includes formula I compound, comprise pharmacologically acceptable salt, and the methods for the treatment of of composition and these compounds of use.
An aspect of of the present present invention relates to formula I compound or pharmaceutically acceptable salt thereof
Wherein:
R
1Be CO
2R
8Or CONR
9R
10
R
2Be hydrogen, alkyl, aminoalkyl group, alkylamino alkyl or dialkyl aminoalkyl;
R
3Be hydrogen, alkyl, aminoalkyl group, alkylamino alkyl or dialkyl aminoalkyl; Or
NR
2R
3Be azetidinyl, pyrrolidyl, piperidyl, piperazinyl, N-(alkyl) piperazinyl, morpholinyl, parathiazan base, homopiperidinyl or high morpholinyl together, and described group is replaced by 0-3 alkyl substituent; Or
NR
2R
3Be together
Or
R
4Be hydrogen or alkyl;
R
5Be hydrogen or alkyl;
Or, R
4And R
5Be oxo together;
R
6Be hydrogen, halogen, alkyl, thiazolinyl, hydroxyl, benzyloxy or alkoxyl group;
R
7Be cycloalkyl;
R
8Be hydrogen or alkyl;
R
9Be hydrogen, alkyl, alkyl SO
2-, cycloalkyl SO
2-, haloalkyl SO
2-, (R
11) (R
12) NSO
2-or (R
13) SO
2-;
R
10Be hydrogen or alkyl;
R
11Be hydrogen or alkyl;
R
12Be hydrogen or alkyl;
R
13Be azetidinyl, pyrrolidyl, piperidyl, piperazinyl, N-(alkyl) piperazinyl, morpholinyl, parathiazan base (thiomorpholinyl), homopiperidinyl (homopiperidinyl) or high morpholinyl (homomorpholinyl); And
R
14Be hydrogen, alkyl, cycloalkyl, (cycloalkyl) alkyl, alkyl-carbonyl, naphthene base carbonyl, halogenated alkyl carbonyl, alkoxy carbonyl, alkyl SO
2-, cycloalkyl SO
2-, haloalkyl SO
2-, aminocarboxyl, (alkylamino) carbonyl, (dialkyl amido) carbonyl, benzyl, benzyloxycarbonyl or pyridyl.
Another aspect of the present invention relates to formula I compound or pharmaceutically acceptable salt thereof, wherein R
1Be CONR
9R
10R
2Be dialkyl aminoalkyl; R
3Be alkyl; Or NR
2R
3Be by morpholinyl or the NR of 2 alkyl substituents replacements together
2R
3Be together
R
4Be hydrogen or alkyl; R
5Be hydrogen or alkyl; Or R
4And R
5Be oxo together; R
6Be alkoxyl group; R
7Be cycloalkyl; R
9Be (R
11) (R
12) NSO
2R
11Be alkyl; R
12Be alkyl; And R
14Be alkyl.
Another aspect of the present invention relates to formula I compound or pharmaceutically acceptable salt thereof, wherein R
1Be CONHSO
2NMe
2R
2Be dimethyl aminoethyl; R
3Be methyl; Or NR
2R
3Be 3,5-dimethylated morpholinyl or NR together
2R
3Be 3-methyl-3 together, 8-diazabicylo [3.2.1] suffering-8-base; R
4Be hydrogen or methyl; R
5Be hydrogen or methyl; Or R
4And R
5Be oxo together; R
6Be methoxyl group; R
7Be cyclohexyl.
Another aspect of the present invention relates to formula I compound, wherein R
1Be CONR
9R
10R
9Be alkyl SO
2-, cycloalkyl SO
2-, haloalkyl SO
2-, (R
11) (R
12) NSO
2-or (R
13) SO
2-; And R
10Be hydrogen.
Another aspect of the present invention relates to formula I compound, wherein R
6Be hydrogen.
Another aspect of the present invention relates to formula I compound, wherein R
6Be methoxyl group.
Another aspect of the present invention relates to formula I compound, wherein R
7Be cyclohexyl.
Another aspect of the present invention relates to formula I compound, wherein R
9Be (R
11) (R
12) NSO
2-or (R
13) SO
2-.
For formula I compound, substituting group (comprises R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14) the scope of any example can be independent the use with respect to the scope of substituent other example.So, the present invention includes the combination of these different aspects.
Except as otherwise noted, these terms have following meaning." alkyl " refers to the straight or branched alkyl be made up of 1 to 6 carbon." thiazolinyl " refers to be formed and had by 2 to 6 carbon the straight or branched alkyl of at least one two key." alkynyl " refers to be formed and had by 2 to 6 carbon the straight or branched alkyl of at least one triple bond." cycloalkyl " refers to the monocycle ring system be made up of 3 to 7 carbon." haloalkyl " comprises all halo isomer with " halogenated alkoxy ", replaces to perhalogeno is plain from single halogen to replace.The term that relates to hydrocarbon part (for example, alkoxyl group) comprises straight chain and the branched chain isomer of hydrocarbon part.Bracket and multiple bracket term are intended to illustrate the bonding relation to those skilled in the art.For example, the term as ((R) alkyl) refers to further be substituted the alkyl substituent that basic R replaces.
The present invention includes all pharmaceutical acceptable salt of described compound.Pharmacologically acceptable salt can not encourage the physiologically active of compound or toxicity and itself as those pharmacologically acceptable salts of pharmacology Equivalent significantly for counter ion wherein.These salt can prepare according to generally there being the machine technology use to be purchased reagent.Some anion salt forms comprise acetate, acistrate (acistrate), benzene sulfonate, bromide, muriate, Citrate trianion, fumarate, glucuronate, hydrobromate, hydrochloride, hydriodate, iodide, lactic acid salt, maleate, mesylate, nitrate, embonate, phosphoric acid salt, succinate, vitriol, tartrate, tosylate and xinafoate (xinofoate).Some cationic salts forms comprise ammonium salt, aluminium salt, benzyl star (benzathine) salt, bismuth salt, calcium salt, choline salt, diethyl amine salt, diethanolamine salt, lithium salts, magnesium salts, meglumine salt, 4-phenyl cyclohexylamine salt, piperazine salt, sylvite, sodium salt, Apiroserum Tham (tromethamine) salt and zinc salt.
Compounds more of the present invention have unsymmetrical carbon (for example compound hereinafter).The present invention includes all stereoisomeric forms in any ratio, comprise mixture such as the racemic modification of enantiomer and diastereomer and steric isomer.Some steric isomers can use method as known in the art to prepare.The three-dimensional heterogeneous mixture of described compound can be separated into independent isomer according to procedures known in the art with the three-dimensional heterogeneous mixture of relevant intermediate.
Synthetic method
Compound can prepare by methods known in the art, and these methods comprise those methods as described below and comprise those versions within those skilled in the art's skill.Some reagent and intermediate are known in the art.Other reagent and intermediate can use the material that obtains easily to prepare by methods known in the art.Be used for describing the synthetic variable (for example, the R substituting group of numbering) of described compound and only be intended to illustrate how to prepare, and should not obscure mutually with the variable that in claims and other paragraph of specification sheets, uses.Following method only is used for the purpose of example, but not intention limits the scope of the invention.
The habitual implication in this area is followed in the abbreviation of using in the scheme usually.The chemical abbreviations of using among specification sheets and the embodiment is defined as follows: " NaHMDS " represents two (the trimethylammonium first is silica-based) sodium amide; " DMF " represents N, dinethylformamide; " MeOH " represents methyl alcohol; " NBS " represents N-bromosuccinimide; " Ar " represents aryl; " TFA " represents trifluoroacetic acid; " LAH " represents lithium aluminum hydride; " BOC " represents tert-butoxycarbonyl; " DMSO " represents dimethyl sulfoxide (DMSO); " h " expression hour; " rt " expression room temperature or retention time (being determined by context); " min " expression minute; " EtOAc " represents ethyl acetate; " THF " represents tetrahydrofuran (THF); " EDTA " represents ethylenediamine tetraacetic acid (EDTA); " Et
2O " the expression ether; " DMAP " represents 4-dimethylaminopyridine; " DCE " expression 1,2-methylene dichloride; " ACN " represents acetonitrile; " DME " expression 1,2-glycol dimethyl ether; " HOBt " expression I-hydroxybenzotriazole hydrate; " DIEA " represents diisopropylethylamine, and " Nf " represents CF
3(CF
2)
3SO
2-; And " TMOF " expression trimethyl orthoformate.
Some compounds can be synthetic by the method shown in the scheme 1.With the oxyhydroxide of nucleophilic to known 5H-indoles [2,1-a] [2] benzo-aza also
Ester is hydrolyzed, and this can generate corresponding carboxylic acid, can use one of multiple known standard amide condition then, makes carboxylic acid and various primary amine or secondary amine coupling, forms corresponding acid amides.Can carry out dehydroxylation to the unsaturated amides that generates and handle, use the perosmic anhydride of catalytic or the co-oxidants (co-oxidant) of ruthenium trichloride (III) and stoichiometry usually, form suitable-diol compound.Then under acidic conditions, use ketone, aldehyde or enol ether as reactant, to described suitable-glycol carries out cyclisation, forms 1,3-dioxolane compound.Alternatively, can under alkaline condition, use the reactant that has two leavings groups in same carbon (described carbon atom is subjected to nucleophillic attack easily), form 1,3-dioxolane (or dioxolane ketone) compound.
Scheme 1.
Alternatively, for obtaining identical molecule, can change the order of above-mentioned steps, as shown in scheme 2 and 3.Scheme 2 shown, can be before forming acyl group sulphonamide/sulphonamide part, and from known 5H-indoles [2,1-a] [2] benzo-aza also
Ester, carboxylic acid begin, and form acid amides, carry out dihydroxy and form dioxolane (dioxolane ketone).Acyl group sulphonamide/sulphonamide can followingly form: by described ester is hydrolyzed, use suitable coupling reagent then, for example CDI or EDC and sulphonamide/sulphonamide carry out coupling.The route that shows in the scheme 3 is by using TFA, to 5H-indoles [2,1-a] [2] benzo-aza also
Diester carries out selective hydrolysis and begins, and this can generate aryl carboxylic acid.Described aryl carboxylic acid can with sulphonamide/sulphonamide coupling, as mentioned above the acyl group sulphonamide/sulphonamide that generates is carried out dihydroxy and cyclisation then, form dioxolane (or dioxolane ketone) compound.Described ester is hydrolyzed, can forms carboxylic acid, in the end a step is carried out the acid amides coupling.
Scheme 2.
Scheme 3.
Biological method
When measuring in following HCV RdRp measures, compound of the present invention has represented the activity of antagonism HCVNS5B.
To HCV NS5B RdRp clone, expression and purifying
To the cDNA that the NS5B albumen of HCV genotype 1b is encoded be cloned in the pET21a expression vector.For improving solubleness, described protein is expressed, so that 18 amino acid C-ends block (18amino acid C-terminal truncation).(the E.coli competent cell line) BL21 (DE3) of competent escherichia coli cell system is used for described protein expression.Make culture about 4 hours of 37 ℃ of growths, the optical density(OD) that reaches 600 nanometers up to culture is 2.0.Make culture be cooled to 20 ℃, and induce with 1mMIPTG.Adding fresh penbritin to ultimate density is 50 mcg/ml, and makes cell 20 ℃ of grow overnight.
Make cell precipitation (3 liters) dissolving for purifying, obtain the purified NS5B of 15-24 milligram.Molten born of the same parents' damping fluid is by 20mM Tris-HCl (pH 7.4), 500mM NaCl, 0.5%Triton X-100,1mM DTT, 1mM EDTA, 20% glycerine, 0.5 mg/ml N,O-Diacetylmuramidase, 10mM MgCl
2, 15 mcg/ml deoxyribonuclease Is and fully TM proteinase inhibitor tablet (Roche) form.After adding molten born of the same parents' damping fluid, the using-system homogenizer makes through freezing cell precipitation and suspends again.In order to reduce the viscosity of sample, use the little tip (microtip) that links to each other with the Branson processor for ultrasonic wave to make the separatory that waits of lysate accept ultrasonication on ice.Through the lysate of ultrasonication 4 ℃ with 100,000 * g centrifugal 1 hour, and filter through 0.2 micron filter unit (Corning).
Use three continuous chromatographic steps to come protein purification: heparin-agarose CL-6B, PolyU sepharose 4B and HiTrap SP agarose (Pharmacia).The chromatogram damping fluid is identical with molten born of the same parents' damping fluid, but does not contain N,O-Diacetylmuramidase, deoxyribonuclease I, MgCl
2Or proteinase inhibitor, and the NaCl concentration of damping fluid is adjusted according to the requirement that protein is loaded on the chromatographic column.Each chromatographic column is with NaCl gradient liquid wash-out, and the length of described gradient liquid changes between 5 to 50 column volumes, and this depends on the type of chromatographic column.Behind final chromatographic step, resulting enzyme purity＞90% (analyzing based on SDS-PAGE).Enzyme such as is divided at separatory, and is stored in-80 ℃.
Standard HCV NS5B RdRp enzymatic determination
Carrying out HCV RdRp genotype 1b in 96 orifice plates (Costar 3912) under final volume is the situation of 60 microlitres measures.Measure damping fluid by 20mM Hepes (pH 7.5), 2.5mM KCl, 2.5mMMgCl
2, 1mM DTT, 1.6 RNAse of unit inhibitor (PromegaN2515), 0.1 mg/ml BSA (Promega R3961) and 2% glycerine forms.All compounds serial dilution in DMSO (3 times) and further dilution in water are so that the ultimate density of DMSO in mensuration is 2%.HCV RdRp genotype 1b enzyme uses with the ultimate density of 28nM.Poly-A (polyA) template is used with 6nM, and biotinylated few dT12 primer uses with the ultimate density of 180nM.Template is (Amersham27-4110) that is commercially available.Biotinylated primer is prepared by Sigma Genosys.3H-UTP uses when 0.6 μ Ci (the total UTP of 0.29 μ M).Come initiation reaction by adding enzyme, hatched 60 minutes at 30 ℃, and stop by adding the 50mM EDTA that 25 microlitres contain SPA bead (4 micrograms/microlitre, Amersham RPNQ 0007).Behind incubated at room＞1 hour, plate is read at Packard Top Count NXT.
Modified HCV NS5B RdRp enzymatic determination
Modified enzymatic determination is basically according to carrying out like that about standard enzyme mensuration is described, different is, biotinylated few dT12 primer is captured in advance on the SPA bead of streptavidin (streptavidin) coating, its mode is that primer and bead are mixed in measuring damping fluid, and incubated at room one hour.Centrifugally remove unconjugated primer.The bead of being combined with primer is suspended in the 20mM Hepes damping fluid (pH 7.5) again, and is that the ultimate density of 20nM and bead is used for measuring when being 0.67 microgram/microlitre in the ultimate density of primer.Addition sequence in the mensuration is as follows: enzyme (14nM) is added in the diluted compound, then adds template (0.2nM), 3H-UTP (0.6 μ Ci, 0.29 μ M) and the mixture of the bead of being combined with primer, with initiation reaction, institute is ultimate density to concentration.Make and be reflected at 30 ℃ and carried out 4 hours.
The IC of compound
50Value uses seven kinds of different [I] ([I] is inhibition concentration) to determine.User's formula y=A+ ((B-A)/(1+ ((C/x) ^D))) calculates IC by restraining effect
50Value.
FRET measures preparation
In order to carry out HCV FRET screening assay, use 96 porocyte culture plates.The FRET peptide (Anaspec, and Inc.) (Taliani et al., Anal.Biochem.1996,240,60-67) containing the fluorescence donor near the one end is EDANS, and to contain acceptor near the other end be DABCYL.Shift the fluorescent quenching that (RET) makes described peptide by the intermolecular resonance energy between donor and the acceptor, but when NS3 proteolytic enzyme made described peptide cracking, the RET cancellation no longer took place in product, and the fluorescence of donor becomes apparent.Mensuration reagent is prepared as follows: the plain molten born of the same parents' reagent of enzyme cell culture of 5 * cell fluorescence (cell Luciferase cell culture lysis reagent) that will derive from Promega (#E153A) is used dH
2O is diluted to 1 *, add NaCl to being 150mM finally, and the FRET peptide is diluted to from the 2mM storing solution finally is 20 μ M.
In order to prepare plate, have or do not have extra large Matthiola incana luciferase (Renilla luciferase) report subbase because of HCV replicon cell trypsin treatment, and place each holes of 96 orifice plates, wherein will be added to the 3rd row through the test compounds of titration to the 12nd row; The 1st row and the 2nd are listed as and contain control compound (HCV proteinase inhibitor), and row of the end contains the cell that does not have compound.Then, plate is placed 37 ℃ CO
2In the incubator.
Measure
After adding above-mentioned test compounds (FRET measures preparation), at different time plate is taken out, and add the Alamar blue solution in each hole (Trek Diagnostics, #00-100), as Cytotoxic measuring method.After in Cytoflour 4000 instruments (PE Biosystems), reading, plate is washed with PBS, be used for FRET mensuration by in each hole, adding the above-mentioned FRET peptide mensuration reagent of 30 microlitres (FRET measures preparation) then.Then, plate is placed Cytoflour 4000 instruments, it has been configured to excitation wavelength is 490nm for the 340nm/ emission wavelength, last 20 circulations with automatic mode, and plate reads in dynamic mode.Typically, at the signal that reads back use end point analysis noise is at least three times.Perhaps, after the Alamar blueness reads, plate is washed with PBS, add and do not have phenol red 50 microlitre DMEM (high glucose), use Promega Dual-Glo Luciferase Assay System then, plate is used for luciferase assay.
By relative HCV replicon restraining effect and relative cytotoxicity values being carried out quantitative compound is analyzed.In order to calculate cytotoxicity values, be 100% nontoxicity with the average A lamar blue-fluorescence signal sets that derives from control wells.Then, with each signal in each compound test hole divided by the average control signal and multiply by 100%, to determine cytotoxicity per-cent.In order to calculate HCV replicon inhibiting value, average background is worth comfortable two holes containing maximum amount HCV proteinase inhibitor when finishing of measuring.These values are similar to those values that derive from natural Huh-7 cell.
Then, background value is deducted from the average signal that derives from control wells, and this value is used as 100% activity.Then, with each signal in each compound test hole after divided by background deduction the average control value and multiply by 100%, to determine active per-cent.EC with the proteinase inhibitor titration
50Value is calculated to be and can makes FRET or uciferase activity reduce by 50% concentration.Be that cytotoxicity per-cent and active per-cent are used for determining remaining the important compound further analyzed at resulting two values of compound plate.
The representative data of The compounds of this invention is reported in the table 1.
Table 1
A＞0.5 μ M; B 0.02 μ M-0.5 μ M; C＜0.02 μ M, but do not record explicit value; IC
50Value uses pre-cultivation scheme to measure.The EC50 value uses FRET to measure.
Pharmaceutical composition and methods for the treatment of
The compounds of this invention shows the activity of antagonism HCV NS5B, and can be used for treating HCV and HCV infection.Therefore, another aspect of the present invention is a kind of composition, and it comprises formula I compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
Another aspect of the present invention is formula I compound for the preparation of the purposes in the medicine for the treatment of hepatitis C.
Another aspect of the present invention is a kind of composition, and it also comprises the compound with anti-HCV activity.
Another aspect of the present invention is a kind of composition, and the compound that wherein has anti-HCV activity is Interferon, rabbit.In another aspect of the present invention, described Interferon, rabbit is selected from (pegylated) interferon alpha, interferon concensus (consensus interferon), interferon alpha 2A and the lymphoblastoid interferon τ of interferon alpha 2B, PEGization.
Another aspect of the present invention is a kind of composition, and the compound that wherein has anti-HCV activity is S-Neoral.In another aspect of the present invention, described S-Neoral is cyclosporin A.
Another aspect of the present invention is a kind of composition, and the compound that wherein has anti-HCV activity is selected from interleukin II, interleukin 6, interleukin 12, can improve 1 type helper cell replys the compound of development, RNA interfering, sense-rna, Imiqimod, ribavirin, 5 '-monophosphate inosine dehydrogenase inhibitor, amantadine and Rimantadine.
Another aspect of the present invention is a kind of composition, the function that the compound that wherein has an anti-HCV activity can effectively suppress target infects with treatment HCV, and described target is selected from HCV metalloprotease (HCVmetalloprotease), HCV serine protease (HCV serine protease), HCV polysaccharase (HCVpolymerase), HCV helicase (HCV helicase), HCV NS4B albumen (HCV NS4Bprotein), HCV enters (HCV entry), HCV assembles (HCV assembly), HCV disengages (HCVegress), HCV NS5A albumen (HCV NS5A protein), IMPDH and nucleoside analog (nucleoside analog).
Another aspect of the present invention is a kind of composition, and it comprises formula I compound or pharmaceutically acceptable salt thereof, pharmaceutically acceptable carrier, Interferon, rabbit and ribavirin.
Another aspect of the present invention is a kind of method of inhibition HCV replicon (HCV replicon) function, and it comprises makes the HCV replicon contact with formula I compound or pharmaceutically acceptable salt thereof.
Another aspect of the present invention is a kind of method that suppresses HCV NS5B protein function, and it comprises makes HCV NS5B albumen contact with formula I compound or pharmaceutically acceptable salt thereof.
The method that another aspect of the present invention infects for HCV among the treatment patient, it comprises the formula I compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity to described patient.In another embodiment, described compound can effectively suppress the function of HCV replicon.In another embodiment, described compound can effectively suppress the function of HCV NS5B albumen.
The method that another aspect of the present invention infects for HCV among the treatment patient, it comprises the formula I compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity to described patient, and gives (before, afterwards or simultaneously) another kind and have the compound of anti-HCV activity.
Another aspect of the present invention is that wherein other compound with anti-HCV activity is the method for Interferon, rabbit.
Another aspect of the present invention is the method for the wherein said Interferon, rabbit interferon alpha, interferon concensus, interferon alpha 2A and the lymphoblastoid interferon τ that are selected from interferon alpha 2B, PEGization.
Another aspect of the present invention is that wherein other compound with anti-HCV activity is the method for S-Neoral.
Another aspect of the present invention is that wherein said S-Neoral is the method for cyclosporin A.
Another aspect of the present invention is that wherein other compound with anti-HCV activity is selected from interleukin II, interleukin 6, interleukin 12, can improves the method that 1 type helper cell is replied the compound of development, RNA interfering, sense-rna, Imiqimod, ribavirin, 5 '-monophosphate inosine dehydrogenase inhibitor, amantadine and Rimantadine.
Another aspect of the present invention can effectively suppress the method that the target function infects with treatment HCV for other compound with anti-HCV activity wherein, and described target is selected from that HCV metalloprotease, HCV serine protease, HCV polysaccharase, HCV helicase, HCV NS4B albumen, HCV enter, HCV assembles, HCV disengages, HCV NS5A albumen, IMPDH and nucleoside analog.
Another aspect of the present invention can effectively suppress hit target function but not suppress the method for the function of HCVNS5B albumen of HCV life circulation for other compound with anti-HCV activity wherein.
" treatment effectively " refers to provide significant patient's benefit needed medication amount, as the medical practitioner in hepatitis and the HCV infection field understands.
" patient " refers to by HCV virus infection and the people that are suitable for treating, as the medical practitioner in hepatitis and the HCV infection field understands.
" treatment ", " therapy ", " dosage regimen ", " HCV infection " and relational language use as the medical practitioner in hepatitis and the HCV infection field understands.
Compound of the present invention generally gives with the form of pharmaceutical composition, and described composition comprises compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier for the treatment of significant quantity, and can contain conventional vehicle.The treatment significant quantity is for providing significant patient's benefit needed amount.Pharmaceutically acceptable carrier is to have the conventional known carrier that can accept security.Composition is contained all common solid form and liquid forms, comprises capsule, tablet, lozenge and powder agent and liquid suspension, syrup, elixir and solution.Composition uses general preparation technique to prepare, and conventional vehicle (such as tackiness agent and wetting agent) is generally used for composition with medium (such as water and alcohol).
Solids composition is formulated into dose unit usually, and every doses the composition of about 1 to 1000 milligram of active ingredient is provided is preferred.Some examples of dosage are 1 milligram, 10 milligrams, 100 milligrams, 250 milligrams, 500 milligrams and 1000 milligrams.Generally speaking, other medicines can exist by the unit scope similar to employed classical unit scope clinically.Typically, it is 0.25-1000 milligram/unit.
Liquid composition is usually in the dose unit scope.Generally speaking, the unitary dose scope of liquid composition can be the 1-100 mg/ml.Some examples of dosage are 1 mg/ml, 10 mg/ml, 25 mg/ml, 50 mg/ml and 100 mg/ml.Generally speaking, other medicines can exist by the unit scope similar to employed classical unit scope clinically.Typically, it is the 1-100 mg/ml.
All conventional mode of administration are contained in the present invention, and oral methods and parenteral method are preferred.Generally speaking, dosage regimen can be similar to employed other medicines clinically.Typically, every day, dosage can be 1-100 milligram/kg body weight every day.Generally speaking, oral way needs more compound, and the parenteral mode needs less compound.Yet concrete dosage regimen can be judged to determine by rational medicine by the doctor.
The present invention also is encompassed in the method that gives described compound in the combination treatment.Be that described compound can use with can be used for treating the other medicines that hepatitis and HCV infect, but described compound separate use with described other medicines.In these combined methods, compound can arrange in pairs or groups usually other medicines and with every day 1-100 milligram/kg body weight dosage every day give.Other medicines generally can be gone up employed amount by treatment and give.Yet concrete dosage regimen can be judged to determine by rational medicine by the doctor.
Some examples that are suitable for the compound of composition and method are listed in the table 2.
Table 2.
Specific embodiments
The LCMS data:
Stand-by time: gradient time+1 minute
Initial concentration: 0%B is unless point out in addition
Elutriant A:5%CH
3CN/95%H
2O contains 10mM NH
4OAc (being used for post A, D, E and F)
10%MeOH/90%H
2O contains 0.1%TFA (being used for post B and C)
Elutriant B:95%CH
3CN/5%H
2O contains 10mM NH
4OAc (being used for post A, D, E and F)
90%MeOH/10%H
2O contains 0.1%TFA (being used for post B and C)
Post A:Phenomenex 10 μ 4.6x50mm C18
Post B:Phenomenex C18 10 μ 3.0x50mm
Post C:Phenomenex 4.6x50mm C18 10 μ
Post D:Phenomenex Lina C18 5 μ 3.0x50mm
Post E:Phenomenex 5 μ 4.6x50mm C18
Post F:Phenomenex 10 μ C18 4.6x30mm
Preparation property HPLC data:
Gradient: linearity, last 20 minutes, unless point out in addition
Initial concentration: 15%B is unless point out in addition
Finish concentration: 100%B
Elutriant A:5%CH
3CN/95%H
2O contains 10mM NH
4OAc
Elutriant B:95%CH
3CN/5%H
2O contains 10mM NH
4OAc
Post: Sunfire Prep C
18OBD 5 μ 30x100mm
The preparation of following initial substance is found among the US 2007060565.
1) 13-cyclohexyl-3-(methoxyl group)-5H-indoles [2,1-a] [2] benzo-aza also
-6,10-dicarboxylic acid 10-(1,1-dimethyl ethyl) ester 6-methyl ester
2) alkylsulfonyl 13-cyclohexyl-10-[[[(dimethylamino)] amino] carbonyl]-3-methoxyl group-7H-indoles [2,1-a] [2] benzo-aza also
-6-carboxylic acid methyl ester
The preparation of following initial substance is found among the WO 2007033175.
3) alkylsulfonyl 13-cyclohexyl-10-[[[(dimethylamino)] amino] carbonyl]-3-methoxyl group-7H-indoles [2,1-a] [2] benzo-aza also
-6-carboxylic acid
The preparation of following initial substance is found among the US 2006166964.
4) (((2S, 6R)-2,6-dimethyl-morpholine-4-yl) carbonyl)-3-(methoxyl group)-6,7-dihydro-7H-indoles is [2,1-a] [2] benzo-aza also for 13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-
-10-methane amide
Intermediate 1
Rac-(5R, 6S)-13-cyclohexyl-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6,10-dicarboxylic acid 10-(1,1-dimethyl ethyl) ester 6-methyl ester.To 13-cyclohexyl-3-(methoxyl group)-7H-indoles [2,1-a] [2] benzo-aza also
(400mg, 0.80mmol) (234mg 2.0mmol) in the slurries in THF (5mL), adds H to-6,10-dicarboxylic acid 10-(1,1-dimethyl ethyl) ester 6-methyl ester with 4-methylmorpholine N-oxide compound
2O (0.20mL) and OsO
4(0.20mL, the OsO of 2.5%w/w
4T-BuOH solution).Reaction mixture at stirring at room 2h, is used saturated Na
2S
2O
3(～5mL) quencher was stirred 1 hour then (aqueous solution).Separate each layer, water layer extracts with THF (2x5mL).The organic layer that merges is concentrated, and resistates is dissolved among the DMF (2mL), use H
2O (～4mL) handle.Solid collected by filtration, and generation rac-(5R, 6S)-13-cyclohexyl-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6,10-dicarboxylic acid 10-(1,1-dimethyl ethyl) ester 6-methyl ester (413mg, 0.77mmol, 96%) is yellow solid, uses this product and is not further purified.
1HNMR (300MHz, CD
3OD) δ 1.22-2.19 (m, 10H), 1.65 (s, 9H), 2.87-3.12 (m, 2H), 3.53 (d, J=15.0Hz, 1H), 3.68 (s, 3H), 3.93 (s, 3H), 4.63 (d, J=15.0Hz, 1H), 7.05 (dd, J=8.4,2.9Hz, 1H), 7.36-7.43 (m, 2H), 7.65 (dd, J=8.4,1.1Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 7.91 (br s, 1H) .LCMS:m/e 536 (M+H)
+, retention time 3.11 minutes, post D, 4 minutes gradients.
Intermediate 2
Rac-(3aR, 14bS)-10-cyclohexyl-2,2-dimethyl-13-(methoxyl group)-4H-[1,3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-3a, 7 (14bH)-dicarboxylic acid 7-(1,1-dimethyl ethyl) ester 3a-methyl ester.(5R, 6S)-13-cyclohexyl-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also to rac-
(30mg 0.056mmol) in the solution in THF (1mL), adds 2-methoxyl group propylene (0.2mL) to-6,10-dicarboxylic acid 10-(1,1-dimethyl ethyl) ester 6-methyl ester, adds TsOH monohydrate (5mg) then.The reaction mixture stirring is spent the night, then concentrate drying.Resistates is dissolved among the DMSO/MeOH, through preparation property HPLC purifying, obtain rac-(3aR, 14bS)-10-cyclohexyl-2,2-dimethyl-13-(methoxyl group)-4H-[1,3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-3a, 7 (14bH)-dicarboxylic acid 7-(1,1-dimethyl ethyl) ester 3a-methyl ester (17mg, 0.030mmol, 53%) are yellow solid.
1HNMR (300MHz, CDCl
3) δ 0.32 (s, 3H), 0.80-2.16 (m, 10H), 1.33 (s, 3H), 1.60 (s, 9H), 2.83-2.95 (m, 1H), 3.85 (s, 3H), 3.87 (s, 3H), 4.00 (d, J=14.8Hz, 1H), 4.46 (d, J=14.8Hz, 1H), 5.21 (s, 1H), 7.00 (d, J=2.6Hz, 1H), 7.04 (dd, J=8.4,2.6Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.67 (dd, J=8.4,1.1Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.98 (br s, 1H) .LCMS:m/e 576 (M+H)
+, retention time 4.28 minutes, post A, 4 minutes gradients.
Intermediate 3
Rac-(5R, 6S)-13-cyclohexyl-10-((((dimethylamino) alkylsulfonyl) amino) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6-carboxylic acid methyl ester.To 13-cyclohexyl-10-[[[(dimethylamino) alkylsulfonyl] amino] carbonyl]-3-methoxyl group-7H-indoles [2,1-a] [2] benzo-aza also
(70mg, 0.13mmol) (37mg 0.32mmol) in the solution in THF (1mL), adds H to-6-carboxylic acid methyl ester with 4-methylmorpholine N-oxide compound
2O (0.10mL) and OsO
4(0.10mL, the OsO of 2.5%w/w
4T-BuOH solution).Reaction mixture at stirring at room 2h, is used saturated Na
2S
2O
3(aqueous solution) (1h is stirred in～1.5mL) quencher then.Separate each layer, water layer extracts with THF (2x2mL).The organic layer that merges is concentrated; and resistates was dissolved in DMF/MeOH (1: 2; 3mL); filter, and through preparation property HPLC purifying, obtain rac-(5R; 6S)-13-cyclohexyl-10-((((dimethylamino) alkylsulfonyl) amino) carbonyl)-5; 6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6-carboxylic acid methyl ester (62mg, 0.11mmol, 83%) is faint yellow solid.
1HNMR (300MHz, d
6-DMSO) δ 1.07-2.10 (m, 10H), 2.80-2.92 (m, 1H), 2.90 (s, 6H), 3.31-3.39 (m, 1H), 3.57 (s, 3H), 3.86 (s, 3H), 4.65-4.74 (m, 2H), 5.56-5.60 (m, 1H), 5.74-5.80 (m, 1H), 7.07 (dd, J=8.4,2.9Hz, 1H), 7.26 (d, J=2.9Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.63 (dd, J=8.4,1.3Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 8.36 (br s, 1H), 11.38 (s, 1H) .LCMS:m/e 584 (M-H)
-, retention time 1.86 minutes, post A, 4 minutes gradients.
Intermediate 4
Rac-(5R, 6S)-13-cyclohexyl-10-((((dimethylamino) alkylsulfonyl) amino) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6-carboxylic acid.(5R, 6S)-13-cyclohexyl-10-((((dimethylamino) alkylsulfonyl) amino) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also to rac-
-6-carboxylic acid methyl ester (57mg, 0.10mmol) in MeOH/THF (1: 1,2mL) in the solution in, add the 1M NaOH aqueous solution (0.5mL).With reaction mixture sealing, and at 80 ℃ with carry out microwave radiation heating 20 minutes.Reaction is used H with the 1NHCl aqueous solution (0.5mL) quencher
2The O dilution, and concentrate, remove organic solvent.Filter and collect the throw out that generates, and vacuum-drying, rac-(5R obtained; 6S)-13-cyclohexyl-10-((((dimethylamino) alkylsulfonyl) amino) carbonyl)-5; 6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6-carboxylic acid (42mg, 0.074mmol, 73%) is yellow solid.
1H NMR (300MHz, CD
3OD) δ 0.73-2.20 (m, 10H), 2.92-3.05 (m, 1H), 3.02 (s, 6H), 3.54 (d, J=14.8Hz, 1H), 3.93 (s, 3H), 4.71 (d, J=14.8Hz, 1H), 4.94 (s, 1H), 7.05 (dd, J=8.4,2.6Hz, 1H), 7.40 (d, J=2.6Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.59 (dd, J=8.4,1.5Hz, 1H), 7.89 (d, J=8.4Hz, 1H), 8.05 (d, J=1.5Hz, 1H) .LCMS:m/e 572 (M+H)
+, retention time 3.34 minutes, post B, 4 minutes gradients.
Intermediate 5
Rac-(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-(((2S, 6R)-2,6-dimethyl-morpholine-4-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-10-methane amide.(((2S, 6R)-2,6-dimethyl-morpholine-4-yl) carbonyl)-3-(methoxyl group)-6,7-dihydro-7H-indoles is [2,1-a] [2] benzo-aza also to 13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-
(500mg, 0.79mmol) (231mg is 1.97mmol) in THF/H with 4-methylmorpholine N-oxide compound for-10-methane amide
2O (10: 1,5.5mL) in the solution in, add OsO
4(0.50mL, the OsO of 2.5%w/w
4T-BuOH solution, 0.04mmol).Reaction mixture at stirring at room 18h, is used saturated Na
2S
2O
3(aqueous solution) (～10mL) quencher, and stir 6h.Separate each layer, water layer extracts with THF (2x 20mL).The saturated Na of organic layer that merges
2S
2O
3(aqueous solution) (～30mL) and salt solution (30mL) washing, and concentrate.Resistates was dissolved in DMF/MeOH (1: 2; 15mL); filter and through preparation property HPLC purifying; obtain rac-(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-(((2S, 6R)-2; 6-dimethyl-morpholine-4-yl) carbonyl)-5; 6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-10-methane amide (230mg, 0.34mmol, 44%) is orange/yellow solid.
1H NMR (300MHz, CDCl
3) δ 0.99-2.02 (m, 20H), 2.83-2.96 (m, 1H), 3.02 (s, 6H), 3.63-3.73 (m, 2H), 3.89 (s, 3H), 4.20-4.38 (m, 1H), 4.60-4.71 (m, 1H), 5.14-5.26 (m, 1H), 7.04 (dd, J=8.4,2.6Hz, 1H), 7.38 (d, J=8.4Hz, 1H), 7.45 (br s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.79-7.97 (m, 2H) .LCMS:m/e 667 (M-H)
-, retention time 1.98 minutes, post A, 4 minutes gradients.
Intermediate 6
13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-N
6-methyl-3-(methoxyl group)-7H-indoles is [2,1-a] [2] benzo-aza also
-6,10-diformamide.With 13-cyclohexyl-10-[[[(dimethylamino) alkylsulfonyl] amino] carbonyl]-3-methoxyl group-7H-indoles [2,1-a] [2] benzo-aza also
-6-carboxylic acid methyl ester (700mg, 1.27mmol) be dissolved in MeOH//THF (1: 1,14mL) in, and handle with the 1M NaOH aqueous solution (3mL).Reaction mixture is stirred, and heated 15 minutes at 80 ℃ with microwave radiation, be cooled to room temperature then.Clear soln concentrates to remove organic solvent then with the 1M HCl aqueous solution (3mL) neutralization.With resistates and H
2O (10mL) stirs 1h, filters then and collects the solid that generates, and uses H
2The O washing, vacuum-drying then.To these solids, i.e. N
1, N
1, N
2-trimethylammonium ethane-1, the 2-diamines (191mg, 1.88mmol) and in the solution of triethylamine (0.700mL) in DMF (5mL), add HATU (620mg, 1.63mmol).Reaction mixture at stirring at room 10h, is used H then
2O (25mL) and 1M HCl (aqueous solution) (5mL) dilute, and stir 20min.Filter the collecting precipitation thing, use H
2The O washing, dry then, generate the product (960mg) of being with impurity, be yellow powder.With the gross sample (100mg) of product of band impurity be dissolved in MeOH/DMF (3: 1,4mL) in, filter and through preparation property HPLC (H
2O/CH
3CN contains 10mM NH
4The OAc damping fluid) purifying obtains 13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-3-methoxyl group-N
6-methyl-7H-indoles is [2,1-a] [2] benzo-aza also
-6,10-diformamide (78mg, 0.13mmol, 95%) is yellow solid.
1H NMR (300MHz, CD
3OD) δ 1.11-3.07 (m, 24H), 2.99 (s, 6H), 3.50-3.76 (m, 2H), 3.93 (s, 3H), 4.27-4.44 (m, 1H), 5.05-5.25 (m, 1H), 7.05 (s, and 1H) 7.08 (d, J=2.6Hz, 1H), 7.16 (dd, J=8.8,2.6Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.64 (dd, J=8.8,1.5Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 8.16 (br s, 1H) .4Hz, 1H), 8.16 (br s, 1H) .LCMS:m/e 620 (M-H)
-, retention time 2.32 minutes, post A, 4 minutes gradients.
Intermediate 7
Glycol, sulphonamide, amide intermediate
Rac-(5R, 6S)-13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-5,6-dihydroxyl-N
6-methyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6,10-diformamide.To 13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-3-methoxyl group-N
6-methyl-7H-indoles is [2,1-a] [2] benzo-aza also
(200mg, 0.32mmol) (94mg is 0.81mmol) in THF/H with 4-methylmorpholine N-oxide compound for-6,10-diformamide
2O (10: 1,3.3mL) in the solution in, add OsO
4(0.15mL, the OsO of 2.5%w/w
4T-BuOH solution 0.014mmol).Reaction mixture at stirring at room 2h, is added extra OsO then
4(0.15mL, the OsO of 2.5%w/w
4T-BuOH solution, 0.014mmol), then make reaction mixture in stirred overnight at room temperature.The saturated Na of reaction mixture
2S
2O
3(aqueous solution) (1h is stirred in～5mL) quencher then.Separate each layer, water layer extracts with THF (2x4mL).The organic layer that merges is concentrated, the water pulp, solid collected by filtration then, generate rac-(5R, 6S)-13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-5,6-dihydroxyl-N
6-methyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-6,10-diformamide (60mg, 0.091mmol, 28%) is yellow solid, uses this product, and is not further purified.LCMS:m/e 654 (M-H)
-, retention time 2.09 minutes, post A, 4 minutes gradients.
Intermediate 8
13-cyclohexyl-N-[(dimethylamino) alkylsulfonyl]-3-methoxyl group-6-[(3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl]-7H-indoles [2,1-a] [2] benzo-aza also
-10-methane amide.To 13-cyclohexyl-N-[(dimethylamino) alkylsulfonyl]-3-methoxyl group-7H-indoles [2,1-a] [2] benzo-aza also
-10-methane amide-6-carboxylic acid (51mg, 0.095mmol), 3-methyl-3, (34mg is 0.17mmol) and in the stirred solution of triethylamine (0.06mL) in DMF (1.0mL) for 8-diazabicylo [3.2.1] octane dihydrochloride, adding HATU (50mg, 0.13mmol).At stirring at room 2h, (～1mL) dilution is filtered then, and through preparation property HPLC (CH with MeOH with reaction mixture
3CN/H
2O contains 10mMNH
4OAc) purifying obtains 13-cyclohexyl-N-[(dimethylamino) alkylsulfonyl]-3-methoxyl group-6-[(3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl]-7H-indoles [2,1-a] [2] benzo-aza also
-10-methane amide (52mg, 0.08mmol, 85%) is yellow solid.
1H NMR (300MHz, CDCl
3) δ 8.31 (s, 1H), 7.83 (d, J=8.4Hz, 1H), 7.59 (br d, J=8.4Hz, 1H), 7.45 (d, J=8.8Hz, 1H), 7.02 (dd, J=8.8,2.6Hz, 1H), 6.91-6.86 (m, 2H), 5.35-5.16 (m, 1H), 4.34-4.16 (m, 1H), 3.87 (s, 3H), 3.01 (s, 6H), 2.85-1.03 (m, 24H) .LCMS:m/e 644 (M-H)
-, retention time 2.89 minutes, post A, 4 minutes gradients.
Intermediate 9
Rac-(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-((3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-10-methane amide.To 13-cyclohexyl-N-[(dimethylamino) alkylsulfonyl]-3-methoxyl group-6-[(3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl]-7H-indoles [2,1-a] [2] benzo-aza also
(303mg, 0.47mmol) (138mg is 1.2mmol) in THF/H with 4-methylmorpholine N-oxide compound for-10-methane amide
2O (10: 1,4.4mL) in the solution in, add OsO
4(0.45mL, the OsO of 2.5%w/w
4T-BuOH solution, 0.04mmol).Reaction mixture stirring at room 2 days, is used 1M Na then
2S
2O
32h is then stirred in (aqueous solution) (5mL) quencher.Solution extracts (first 10mL, the then EtOAc of 5mL) with EtOAc.The organic layer 1M Na that merges
2S
2O
3(aqueous solution) washing is after concentrating, through preparation property HPLC (CH
3CN/H
2O contains 10mM NH
4OAc) purifying, obtain rac-(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-5; 6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
-10-methane amide (57mg, 0.08mmol, 18%) is yellow solid, and this product directly uses, and is not further purified.LCMS:m/e 680 (M+H)
+, retention time 1.66 minutes, post C, 2 minutes gradients.
Embodiment 1
Rac-(3aR, 14bS)-10-cyclohexyl-N
3a-(2-(dimethylamino) ethyl)-N
7-((dimethylamino) alkylsulfonyl)-N
3a, 2,2-trimethylammonium-13-(methoxyl group)-4H-[1,3] and dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-3a, 7 (14bH)-diformamides.With 2-methoxyl group propylene (0.1mL, 1.0mmol) add to rac-(5R, 6S)-13-cyclohexyl-N
6-(2-(dimethylamino) ethyl)-N
10-((dimethylamino) alkylsulfonyl)-5,6-dihydroxyl-N
6-methyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also
(30mg is 0.045mmol) in the slurries in DCE (1mL) for-6,10-diformamide.Add the p-TsOH monohydrate (1mg, 0.005mmol), and with reaction mixture in stirred overnight at room temperature.(10mg 0.05mmol), stirs 2h with reaction mixture then to add methylene dichloride (1mL) and extra p-TsOH monohydrate.Reaction mixture (1mL) neutralizes with 1N NaOH (aqueous solution), separates each layer then.Organic layer salt water washing concentrates then, and through preparation property HPLC (CH
3CN/H
2O contains 10nM NH
4OAc) purifying, obtain rac-(3aR, 14bS)-10-cyclohexyl-N
3a(2-(dimethylamino) ethyl)-N
7-((dimethylamino) alkylsulfonyl)-N
3a, 2,2-trimethylammonium-13-(methoxyl group)-4H-[1,3] and dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-3a, 7 (14bH)-diformamides (16.7mg, 0.024mmol, 50%) are pale solid.
1H NMR (300MHz, CD
3OD) δ 0.31 (s, 3H), 1.20-2.20 (m, 13H), 2.54 (s, 3H), 2.58 (s, 3H), 2.97 (s, 6H), 2.72-3.11 (m, 5H), 3.50-3.89 (m, 4H), 3.94 (s, 3H), 4.40-4.63 (m, 1H), and 5.47-5.52 (m, 1H), 7.10-7.17 (m, 1H), 7.21-7.27 (m, 1H), 7.33-7.47 (m, H), 7.61-7.67 (m, 1H), and 7.76-7.86 (m, 1H), 8.03-8.09 (m, 1H) .LCMS:m/e 696 (M+H)
+, retention time 3.19 minutes, post B, 4 minutes gradients.
Embodiment 2
Rac-(3aR, 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-(((2R, 6S)-2; 6-dimethyl-morpholine-4-yl) carbonyl)-and 13-(methoxyl group)-2-oxo-3a, 14b-dihydro-4H-[1,3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide.With rac-(5R, 6S)-(((2S, 6R)-2,6-dimethyl-morpholine-4-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also for 13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-
(35mg, 0.052mmol) with 1, (58mg, 0.36mmol) solution in THF (2mL) is sealed in the reaction vessel 1 '-carbonyl dimidazoles-10-methane amide, heats 20min (～50% transformation efficiency) through microwave radiation at 75 ℃ then.Continue heating 40min (～80% transformation efficiency) at 80 ℃.Reaction mixture is cooled to room temperature, concentrate drying, with resistates be dissolved in MeOH (～2mL) in, after the filtration, through preparation property HPLC (CH
3CN/H
2O contains 10mM NH
4OAc) purifying; obtain rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-(((2R; 6S)-2; 6-dimethyl-morpholine-4-yl) carbonyl)-and 13-(methoxyl group)-2-oxo-3a, 14b-dihydro-4H-[1,3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide (20.6mg, 0.030,57%) is white powder.
1H NMR (300MHz, CDCl
3) δ 1.04-2.11 (m, 16H), 2.41-2.55 (m, 1H), 2.80-2.95 (m, 1H), 3.02 (s, 6H), 3.02-3.13 (m, 1H), 3.48-3.82 (m, 2H), 3.90 (s, 3H), 4.05-4.26 (m, 1H), 4.32-4.59 (m, 3H), 5.94 (d, J=14.3Hz, 1H), 7.11 (br d, J=8.4Hz, 1H), 7.20 (d, J=2.2Hz, 1H), 7.30-7.39 (m, 1H), 7.43 (d, J=8.4Hz, 1H), 7.78-7.91 (m, 2H) .LCMS:m/e 693 (M-H)
-, retention time 2.77 minutes, post A, 4 minutes gradients.
Embodiment 3
Rac-(3aR, 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-(((2R, 6S)-2; 6-dimethyl-morpholine-4-yl) carbonyl)-2,2-dimethyl-13-(methoxyl group)-3a, 14b-dihydro-4H-[1; 3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-7-methane amide.To rac-(5R, 6S)-(((2S, 6R)-2,6-dimethyl-morpholine-4-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also for 13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-
(60mg is 0.090mmol) in CH for-10-methane amide
2Cl
2In the solution (3mL), add 2-methoxyl group propylene (0.5mL, 5.2mmol) and TsOHH
2O (50mg.0.26mmol).Reaction soln at stirring at room 2h, behind the concentrate drying, is dissolved among the MeOH, and (C18,500mg MeOH) after the filtration, concentrate, then through preparation property HPLC (CH through the SPE post
3CN/H
2O contains 10mM NH
4OAc) purifying; obtain rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-(((2R; 6S)-2,6-dimethyl-morpholine-4-yl) carbonyl)-2,2-dimethyl-13-(methoxyl group)-3a; 14b-dihydro-4H-[1; 3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-7-methane amide (15.5mg, 0.022,24%) is faint yellow solid.
1H NMR (300MHz, CDCl
3) δ 0.28 (s, 3H), 0.88-2.12 (m, 19H), 2.36-2.49 (m, 1H), 2.85-3.01 (m, 2H), 3.03 (s, 6H), 3.48-3.80 (m, 2H), 3.88 (s, 3H), 3.89-4.04 (m, 1H), 4.22-4.50 (m, 2H), 4.76-4.96 (m, 1H), 5.52-5.59 (m, 1H), 7.01 (dd, J=8.4,2.6Hz, 1H), 7.20-7.33 (m, 2H), 7.37 (d, J=8.4Hz, 1H), 7.78-7.91 (m, 2H) .LCMS:m/e 707 (M-H)
-, retention time 3.26 minutes, post A, 4 minutes gradients.
Embodiment 4
Rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-13-(methoxyl group)-2-oxo-3a; 14b-dihydro-4H-[1; 3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide.(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-((3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also with rac-
(31mg, 0.045mmol) with 1, (120mg, 0.74mmol) solution in TEA (0.1mL) and THF (1mL) is sealed in the reaction vessel 1 '-carbonyl dimidazoles-10-methane amide, heats 2h through microwave radiation at 90 ℃ then.Reaction mixture is cooled to room temperature, behind the concentrate drying, is dissolved among the MeOH, after the filtration, through preparation property HPLC (CH
3CN/H
2O contains 10mM NH
4OAc) purifying.Contain the material of required product again through preparation property HPLC (MeOH/H
2O; contain 10mM TFA) purifying; obtain rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-and 13-(methoxyl group)-2-oxo-3a, 14b-dihydro-4H-[1,3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide (9.5mg, 0.013mmol, 30%) is white solid.
1HNMR (300MHz, CD
3OD) δ 1.20-2.33 (m, 14H), 2.87-3.02 (m, 5H), 3.04 (s, 6H), 3.35-4.52 (m, 3H), 3.96 (s, 3H), 4.23 (br d, J=14.6,1H), 4.75 (br d, J=14.6,1H), 4.95 (br s, 1H), 5.16 (br s, 1H), 6.11 (br s, 1H), 7.26-7.32 (m, 2H), 7.55 (d, J=8.8Hz, 1H), 7.63 (dd, J=8.4,1.5Hz, 1H), 7.94 (d, J=8.4Hz, 1H), 7.99 (br s, 1H) .LCMS:m/e 706 (M+H)
+, retention time 1.56 minutes, post C, 2 minutes gradients.
Embodiment 5
Rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-2; 2-dimethyl-3a-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-13-(methoxyl group)-3a; 14b-dihydro-4H-[1; 3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-7-methane amide.(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-((3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also to rac-
(42mg, 0.062mmol) (0.5mL is 5.2mmol) in CH with 2-methoxyl group propylene for-10-methane amide
2Cl
2In the solution (0.5mL), add TsOHH
2O (5mg.0.026mmol).Reaction soln in stirred overnight at room temperature, behind the concentrate drying, is dissolved among the MeOH, after the filtration, through preparation property HPLC (CH
3CN/H
2O contains 10mM NH
4OAc) purifying; obtain rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-2; 2-dimethyl-3a-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-and 13-(methoxyl group)-3a, 14b-dihydro-4H-[1,3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide (6.7mg, 0.1mmol, 15%) is pale solid.
1H NMR (300MHz, CD
3OD) δ 0.33 (s, 3H), 1.19-2.54 (m, 22H), 2.65-2.78 (m, 0.5H), 2.90-3.02 (m, 2H), 3.03 (s, 6H), 3.16-3.28 (m, 0.5H), 3.91 (d, J=15.0Hz, 0.5H), 3.94 (s, 3H), 4.05 (d, J=15.0Hz, 0.5H), 4.34 (d, J=15.0Hz, 0.5H), 4.58 (d, J=15.0Hz, 0.5H), 4.66-4.74 (m, 1H), 5.15-5.22 (m, 0.5H), 5.45-5.59 (m, 1.5H), 7.15 (dd, J=8.4,2.6Hz, 1H), and 7.22-7.29 (m, 1H), 7.45 (dd, J=8.4Hz, 1H), 7.59 (dd, J=8.4,1.8Hz, 1H), 7.86-7.93 (m, 2H) .LCMS:m/e 718 (M-H)
-, retention time 1.60 minutes, post F, 2 minutes gradients.
Embodiment 6
Rac-(3aR, 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-((3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-13-(methoxyl group)-3a; 14b-dihydro-4H-[1; 3] dioxolane [4,5-d] indoles [2,1-a] [2] benzo-aza also also
-7-methane amide.(5R, 6S)-13-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-6-((3-methyl-3,8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-5,6-dihydroxyl-3-(methoxyl group)-6,7-dihydro-5H-indoles be [2,1-a] [2] benzo-aza also to rac-
(47mg is 0.069mmol) in CH for-10-methane amide
2Cl
2(1mL) and CH
2Br
2In the solution (1mL), add nBu
4N
+I
-(16mg.0.043mmol) and 5.5N NaOH (aqueous solution) (0.6mL).Reaction soln in stirred overnight at room temperature, is concentrated and removes CH
2Cl
2, use CH
2Br
2(1mL) dilution, and in sealed vessel, spend the night in 50 ℃ of stirrings.With the crude product mixture concentrate drying, through preparation property HPLC (MeOH/H
2O; contain 10mMTFA) purifying; obtain rac-(3aR; 14bS)-10-cyclohexyl-N-((dimethylamino) alkylsulfonyl)-3a-((3-methyl-3; 8-diazabicylo [3.2.1] suffering-8-yl) carbonyl)-and 13-(methoxyl group)-3a, 14b-dihydro-4H-[1,3] dioxolane also [4; 5-d] indoles [2,1-a] [2] benzo-aza also
-7-methane amide (14.5mg, 0.21mmol, 30%) is the glassy yellow solid.
1H NMR (300MHz, CD
3OD) δ 1.21-2.39 (m, 16H), 2.74, (s, 3H), and 2.84-2.97 (m, 2H), 3.02 (s, 6H), and 3.44-3.54 (m, 1H), 3.87 (d, J=15.0,1H), 3.95 (s, 3H), 4.08-4.27 (m, 2H), 5.23-5.29 (m, 2H), 5.43-5.46 (m, 1H), 5.93 (d, J=7.7Hz, 1H), and 7.11-7.19 (m, 2H), 7.47 (d, J=8.1Hz, 1H), 7.58 (dd, J=8.4,1.5Hz, 1H), 7.94 (d, J=8.4Hz, 1H), 7.99 (br s, 1H) .LCMS:m/e 692 (M+H)
+, retention time 1.89 minutes, post C, 2 minutes gradients.
It should be obvious to a one skilled in the art that the embodiment that the invention is not restricted to earlier examples explanation, and it can be embodied as other specific form, and not depart from its essential attribute.Therefore, it is desirable to, embodiment will be thought of as exemplary from every side, when mentioning claims but not claims are limited to above-described embodiment.Thereby, be also included within the scope of the present invention in the implication of claims Equivalent and the various variations in the scope.
Claims (14)
1. formula I compound or pharmaceutically acceptable salt thereof
Wherein:
R
1Be CO
2R
8Or CONR
9R
10
R
2Be hydrogen, alkyl, aminoalkyl group, alkylamino alkyl or dialkyl aminoalkyl;
R
3Be hydrogen, alkyl, aminoalkyl group, alkylamino alkyl or dialkyl aminoalkyl; Or
NR
2R
3Be morpholinyl, parathiazan base together, and described group is replaced by 0-3 alkyl substituent; Or
NR
2R
3Be together
Or
R
4Be hydrogen or alkyl;
R
5Be hydrogen or alkyl; Or
R
4And R
5Be oxo together;
R
6Be hydrogen, halogen, alkyl, hydroxyl or alkyl oxy;
R
7Be cycloalkyl;
R
8Be hydrogen or alkyl;
R
9Be hydrogen, alkyl, alkyl SO
2-, haloalkyl SO
2-or (R
11) (R
12) NSO
2-;
R
10Be hydrogen or alkyl;
R
11Be hydrogen or alkyl;
R
12Be hydrogen or alkyl; And
R
14Be hydrogen or alkyl;
Wherein said alkyl refers to that the straight or branched alkyl be made up of 1 to 6 carbon, described cycloalkyl refer to the monocycle ring system of being made up of 3 to 7 carbon.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein R
1Be CONR
9R
10R
2Be dialkyl aminoalkyl; R
3Be alkyl; Or NR
2R
3Be morpholinyl together, described morpholinyl is replaced by 2 alkyl substituents; Or NR
2R
3Be together
R
4Be hydrogen or alkyl; R
5Be hydrogen or alkyl; Or R
4And R
5Be oxo together; R
6Be alkyl oxy; R
7Be cycloalkyl; R
9Be (R
11) (R
12) NSO
2-; R
11Be alkyl; R
12Be alkyl; And R
14Be alkyl.
3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein R
1Be CONHSO
2NMe
2R
2Be dimethyl aminoethyl; R
3Be methyl; Or NR
2R
3Be 3,5-dimethylated morpholinyl together; Or NR
2R
3Be 3-methyl-3 together, 8-diazabicylo [3.2.1] suffering-8-base; R
4Be hydrogen or methyl; R
5Be hydrogen or methyl; Or R
4And R
5Be oxo together; R
6Be methoxyl group; And R
7Be cyclohexyl.
4. the compound of claim 1, wherein R
1Be CONR
9R
10R
9Be alkyl SO
2-, haloalkyl SO
2-or (R
11) (R
12) NSO
2-; And R
10Be hydrogen.
5. the compound of claim 1, wherein R
6Be hydrogen.
6. the compound of claim 1, wherein R
6Be methoxyl group.
7. the compound of claim 1, wherein R
7Be cyclohexyl.
8. the compound of claim 1, wherein R
9Be (R
11) (R
12) NSO
2-.
9. the compound of claim 1, it has following stereochemistry character
10. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is selected from:
11. a composition, it comprises the described compound or pharmaceutically acceptable salt thereof of claim 1 and pharmaceutically acceptable carrier.
12. the described composition of claim 11, it also comprises at least a extra compound that HCV is had the treatment benefit, and wherein said compound is selected from Interferon, rabbit, S-Neoral, interleukin-, HCV inhibitors of metalloproteinase, HCV serpin, HCV AG14361, HCV helicase inhibitor, HCV NS4B protein inhibitor, HCV entry inhibitor, HCV assembling inhibitor, HCV and disengages inhibitor, HCV NS5A protein inhibitor, HCV NS5B protein inhibitor and HCV replicon inhibitor.
13. the compound of claim 1 for the preparation of the treatment hepatitis C infection medicine in purposes.
14. the purposes of claim 13, it also comprises at least a extra compound that HCV is had the treatment benefit of administration, and wherein said compound is selected from Interferon, rabbit, S-Neoral, interleukin-, HCV inhibitors of metalloproteinase, HCV serpin, HCV AG14361, HCV helicase inhibitor, HCV NS4B protein inhibitor, HCV entry inhibitor, HCV assembling inhibitor, HCV and disengages inhibitor, HCV NS5A protein inhibitor, HCV NS5B protein inhibitor and HCV replicon inhibitor.
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| CN101087761A (en) * | 2004-10-26 | 2007-12-12 | P.安杰莱蒂分子生物学研究所 | Tetracyclic indole derivatives as antiviral agents |
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| US7399758B2 (en) * | 2005-09-12 | 2008-07-15 | Meanwell Nicholas A | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| US7473688B2 (en) | 2005-09-13 | 2009-01-06 | Bristol-Myers Squibb Company | Indolobenzazepine HCV NS5B inhibitors |
| US7456165B2 (en) | 2006-02-08 | 2008-11-25 | Bristol-Myers Squibb Company | HCV NS5B inhibitors |
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| US7456166B2 (en) | 2006-05-17 | 2008-11-25 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
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| US7452876B2 (en) | 2006-06-08 | 2008-11-18 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
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2009
- 2009-03-26 JP JP2011502068A patent/JP2011515496A/en active Pending
- 2009-03-26 KR KR1020107023921A patent/KR20100134699A/en not_active Application Discontinuation
- 2009-03-26 CN CN2009801110082A patent/CN101981038B/en not_active Expired - Fee Related
- 2009-03-26 MX MX2010010245A patent/MX2010010245A/en active IP Right Grant
- 2009-03-26 WO PCT/US2009/038441 patent/WO2009120890A1/en active Application Filing
- 2009-03-26 EP EP09725130.0A patent/EP2268643B1/en not_active Not-in-force
- 2009-03-26 US US12/922,927 patent/US8138171B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101087761A (en) * | 2004-10-26 | 2007-12-12 | P.安杰莱蒂分子生物学研究所 | Tetracyclic indole derivatives as antiviral agents |
| WO2007140254A2 (en) * | 2006-05-25 | 2007-12-06 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine hcv ns5b inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100134699A (en) | 2010-12-23 |
| US8138171B2 (en) | 2012-03-20 |
| WO2009120890A1 (en) | 2009-10-01 |
| US20110020277A1 (en) | 2011-01-27 |
| CN101981038A (en) | 2011-02-23 |
| EP2268643B1 (en) | 2014-08-06 |
| AU2009228214A1 (en) | 2009-10-01 |
| EP2268643A1 (en) | 2011-01-05 |
| MX2010010245A (en) | 2010-10-05 |
| JP2011515496A (en) | 2011-05-19 |
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